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XPOT Disruption Suppresses TNBC Growth through Inhibition of Specific tRNA Nuclear Exportation and TTC19 Expression

Huijuan Dai1, Xiaomei Yang2, Xiaonan Sheng1

  • 1Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China.

International Journal of Biological Sciences
|November 6, 2023
PubMed

Insights

Exportin-T (XPOT) facilitates triple-negative breast cancer (TNBC) cell proliferation by regulating tRNA nuclear export and protein synthesis. Targeting XPOT offers a potential therapeutic strategy for TNBC.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Transfer RNAs (tRNAs) play a role in cancer development, but their specific modulation in triple-negative breast cancer (TNBC) is unclear.
  • Exportin-T (XPOT), a protein involved in nuclear export, has been linked to poor prognosis in breast cancer.

Purpose of the Study:

  • To investigate the role of XPOT in the progression of triple-negative breast cancer (TNBC).
  • To elucidate the mechanism by which XPOT influences tRNA transport and protein synthesis in TNBC cells.

Main Methods:

  • RNA sequencing (RNA-seq) to analyze gene expression and identify XPOT's role in TNBC cell processes.
  • High-throughput tRNA sequencing to identify specific tRNAs affected by XPOT.
  • Codon preferential analysis and mass spectrometry to determine the impact of tRNA transport on protein translation.

Main Results:

  • XPOT knockdown inhibited TNBC cell proliferation and was linked to cytokinesis completion.
  • XPOT specifically mediated the nucleocytoplasmic transport of a subset of tRNA isodecoders, including tRNA-Ala-AGC-10-1.
  • XPOT-mediated transport of tRNA-Ala-AGC-10-1 promoted the translation of TPR Repeat Protein 19 (TTC19), crucial for TNBC proliferation and cytokinesis.

Conclusions:

  • XPOT regulates TNBC cell proliferation through a novel mechanism involving preferential nuclear export of specific tRNAs.
  • This mechanism coordinates tRNA localization and mRNA translation, impacting TNBC progression.
  • XPOT represents a potential therapeutic target for TNBC treatment.
Keywords:
XPOTcytokinesismRNA translationtRNA nucleo-cytoplasmic transporttriple negative breast cancer

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